Hematopoietic stem cell gene therapy has already made an impact on the treatment of several inherited diseases. Patients with X-linked SCID (1), adenosine deaminase deficiency (2), X-linked adeno-leukodystrophy (3) and beta thalassemia (4) have been cured of their disease or their clinical status was dramatically improved. However, genotoxic side effects secondary to vector-mediated insertional mutagenesis appeared in a proportion of patients, including T-cell leukemia in almost 25% of patients treated in the X-linked SCID gene therapy trials (1). Genotoxicity arises from the activation of cellular oncogenes by the enhancers in the viral vectors (reviewed in 5,6). Various approaches have been attempted to decrease the risks of insertional mutagenesis.